Wayne K. Potts

The evolution of mating preferences and major histocompatibility complex genes

House mice prefer mates genetically dissimilar at the major histocompatibility complex (MHC). The highly polymorphic MHC genes control immunological self/nonself recognition; therefore, this mating preference may function to provide “good genes” for an individuals offspring. However, the evidence for MHC‐dependent mating preferences is controversial, and its function remains unclear. Here we provide a critical review of the studies on MHC‐dependent mating preferences in mice, sheep, and humans and the possible functions of this behavior. There are three adaptive hypotheses for MHC‐dependent mating preferences. First, MHC‐disassortative mating preferences produce MHC‐heterozygous offspring that may have enhanced immunocompetence. Although this hypothesis is not supported by tests of single parasites, MHC heterozygotes may be resistant to multiple parasites. Second, we propose that MHC‐dependent mating preferences enable hosts to provide a “moving target” against rapidly evolving parasites that escape immune recognition (the Red Queen hypothesis). Such parasites are suspected to drive MHC diversity through rare‐allele advantage. Thus, the two forms of parasite‐mediated selection thought to drive MHC diversity, heterozygote and rare‐allele advantage, will also favor MHC‐dependent mating preferences. Finally, MHC‐dependent mating preferences may also function to avoid inbreeding; a hypothesis consistent with other evidence that MHC genes play a role in kin recognition.

MHC heterozygosity confers a selective advantage against multiple-strain infections

Genetic heterozygosity is thought to enhance resistance of hosts to infectious diseases, but few tests of this idea exist. In particular, heterozygosity at the MHC, the highly polymorphic loci that control immunological recognition of pathogens, is suspected to confer a selective advantage by enhancing resistance to infectious diseases (the “heterozygote advantage” hypothesis). To test this hypothesis, we released mice into large population enclosures and challenged them with multiple strains of Salmonella and one of Listeria. We found that during Salmonella infections with three avirulent strains, MHC heterozygotes had greater survival and weight than homozygotes (unlike sham controls), and they were more likely to clear chronic Salmonella infection than homozygotes. In laboratory experiments, we found that MHC heterozygosity enhanced the clearance of multiple-strain Salmonella infections. Yet, contrary to what is widely assumed, the benefits of heterozygosity were due to resistance being dominant rather than overdominant, i.e., heterozygotes were more resistant than the average of parental homozygotes, but they were not more resistant than both. The fact that MHC heterozygotes were more resistant to infection and had higher fitness than homozygotes provides a functional explanation for MHC-disassortative mating preferences.

Chemical signals and parasite-mediated sexual selection

Research into visual and acoustic signals has demonstrated that exaggerated sexual displays often provide an honest indicator of a males resistance to parasites. Recent studies with rodents and humans now suggest that chemosensory signals also reveal a males disease resistance and his genetic compatibility. Our understanding of sexual selection has been greatly enriched by considering the mechanisms underlying visual and acoustic displays, and recent advances in chemical communication will help to determine what kind of information is revealed by an individuals scent.

MHC-disassortative mating preferences reversed by cross-fostering.

House mice (Mus musculus domesticus) avoid mating with individuals that are genetically similar at the major histocompatibility complex (MHC). Mice are able recognize MHC–similar individuals through specific odour cues. However, to mate disassortatively for MHC genes, individuals must have a referent, either themselves (self–inspection) or close kin (familial imprinting), with which to compare the MHC identity of potential mates. Although studies on MHC–dependent mating preferences often assume that individuals use self–inspection, laboratory experiments with male mice indicate that they use familial imprinting, i.e. males learn the MHC identity of their family and then avoid mating with females carrying ‘familial’ MHC alleles. To determine if female mice use familial imprinting, we cross–fostered wild–derived female mouse pups into MHC–dissimilar families, and then tested if this procedure reversed their mating preferences compared with in–fostered controls. Our observations of the females mating behaviour in seminatural social conditions and the genetic typing of their progeny both indicated that females avoided mating with males carrying MHC genes of their foster family, supporting the familial imprinting hypothesis. We show that MHC–dependent familial imprinting potentially provides a more effective mechanism for avoiding kin matings and reducing inbreeding than self–inspection.

Evolution of MHC genetic diversity: a tale of incest, pestilence and sexual preference

Evidence from the house mouse (Mus) suggests that the extreme diversity of genes of the major histocompatibility complex (MHC) results from three different forms of selection involving infectious disease (pestilence), inbreeding (incest) and MHC-based mating (sexual) preferences. MHC-based disassortative mating preferences are presumed to have evolved because they reduce homozygosity throughout the genome, and particularly within loci linked to the MHC. Progeny derived from such disassortative matings would enjoy increased fitness because of both reduced levels of inbreeding depression and increased resistance to infectious disease arising from their increased MHC heterozygosity.

Evolution of diversity at the major histocompatibility complex

Recent evidence from both population data and DNA sequence analyses indicates that the unprecedented genetic diversity found at MHC loci is selectively maintained in contemporary natural populations, although the strength and nature of this selection are currently unclear. Due to the critical role played by MHC molecules in immune recognition, it is generally assumed that some form of parasite-driven selection is operating. However, the general failure to implicate MHC in the susceptibility to specific infectious diseases has been troubling, and may indicate that selection is too weak to detect directly. Alternatively, strong selection can be reconciled by a variety of factors including the amplification of minor (disease-based) vigor differences into large fitness differences by intraspecific competition, or non-disease-based selection such as mating preferences and selective abortion.

Major histocompatibility complex heterozygote superiority during coinfection.

ABSTRACT Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition, and many alleles confer susceptibility to infectious and autoimmune diseases. How these deleterious alleles persist in populations is controversial. One hypothesis postulates that MHC heterozygote superiority emerges over multiple infections because MHC-mediated resistance is generally dominant and many allele-specific susceptibilities to pathogens will be masked by the resistant allele in heterozygotes. We tested this hypothesis by using experimental coinfections with Salmonella enterica (serovar Typhimurium C5TS) and Theilers murine encephalomyelitis virus (TMEV) in MHC-congenic mouse strains where one haplotype was resistant to Salmonella and the other was resistant to TMEV. MHC heterozygotes were superior to both homozygotes in 7 out of 8 comparisons (P = 0.0024), and the mean standardized pathogen load of heterozygotes was reduced by 41% over that of homozygotes (P = 0.01). In contrast, no heterozygote superiority was observed when the MHC haplotype combinations had similar susceptibility profiles to the two pathogens. This is the first experimental evidence for MHC heterozygote superiority against multiple pathogens, a mechanism that would contribute to the evolution of MHC diversity and explain the persistence of alleles conferring susceptibility to disease.

Communal nesting and communal nursing in house mice, Mus musculus domesticus

Abstract The functional significance of communal nesting and nursing is poorly understood. Female house mice often communally nest, and within these communal nests females appear to indiscriminately nurse all pups, a rare trait for any mammal. In this study, the hypothesis that communal nesting provides protection from conspecific infanticide was tested and supported in semi-natural populations of house mice. Conspecific infanticide in single-mother nests (69%, N = 412) was twice that in communal nests (33%, N = 508). Because this major benefit of communal nesting does not require communal nursing, direct benefits to communal nursing itself were tested. Most proposed benefits should result in heavier weaning weights, but no differences were found between communal and single nests in the semi-natural populations. If communal nursing is to be avoided in communal nests, dams must recognize their own pups. Retrieval tests conducted in the laboratory produced equivocal results. Dams discriminated between pups that differed in age, but not between their own and other age-matched pups. The major survival advantage of communal nesting, coupled with the failure to find nutritional advantages for communally nursed pups, supports a recent suggestion that communal nursing is an unavoidable consequence of communal nesting. This hypothesis is further strengthened by data indicating that communal nesting partners tend to be kin, thereby providing inclusive fitness benefits to communal nursing. Although costs of communal nursing were proposed and tested, no such costs were found. We also show from 15 observations of infanticide that all classes of adults (territorial and non-territorial males, pregnant and non-pregnant females) are infanticidal. These observations are in conflict with previous laboratory studies.

Pathogen‐Based Models Favoring MHC Genetic Diversity

We present six models that are currently the most likely ways that pathogens might favor the evolution of MHC genetic diversity. Although each model makes one or more unique predictions, the current lack of crucial data prevents distinguishing the relative importance of each model. However, this first-time organization of these models should contribute to the design of critical experiments. This synthetic review yields at least three essentially new ideas. First, MHC-dependent immune recognition may be sufficiently redundant to render it essentially escape-proof by pathogens. Second, the four models based on pathogen escape do not work (or work weakly) for diversifying class II genes, unless class II-restricted cytotoxic T-cells are important, an idea that is controversial. Third, pathogen-escape events have traditionally been thought to result in only frequency-dependent selection but here we show that heterozygote advantage is an inevitable consequence of such pathogen evasion. Therefore, the controversy over the relative importance of these two forms of balancing selection is largely a false dichotomy.

Untrained mice discriminate MHC-determined odors

Immune recognition occurs when foreign antigens are presented to T-lymphocytes by molecules encoded by the highly polymorphic genes of the major histocompatibility complex (MHC). House mice (Mus musculus) prefer to mate with individuals that have dissimilar MHC genes. Numerous studies indicate that mice recognize MHC identity through chemosensory cues; however, it is unclear whether odor is determined by classical, antigen-presenting MHC loci or closely linked genes. Previous studies have relied on training laboratory mice and rats to distinguish MHC-associated odors, but there are several reasons why training experiments may be inappropriate assays for testing if MHC genes affect odor. The aim of this study was to determine whether classical MHC genes affect individual odors and whether wild-derived mice can detect MHC-associated odors without training. In the first experiment, we found that wild-derived mice can be trained in a Y-maze to detect the odors of mice that differ genetically only in the MHC region. In the second and third experiments, we used a naturalistic habituation assay and found that wild-derived mice can, without training, distinguish the odors of mice that differ genetically only at one classical MHC locus (dm2 mutants).